Abstract
Structure-activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (11n) as a potent (HWB TNF-alpha = 0.67 microM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey.
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
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Administration, Oral
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Animals
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Bronchoconstriction / drug effects
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Bronchoconstriction / physiology
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Cell Line, Transformed / drug effects
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Emetics / pharmacology
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Ferrets
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Guinea Pigs
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Half-Life
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Humans
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Inhibitory Concentration 50
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Ovalbumin / pharmacology
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Phosphodiesterase Inhibitors / chemical synthesis*
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Phosphodiesterase Inhibitors / metabolism
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Phosphodiesterase Inhibitors / pharmacokinetics
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Phosphodiesterase Inhibitors / pharmacology*
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Pyridines / chemical synthesis*
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Pyridines / metabolism
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Pyridines / pharmacokinetics
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Pyridines / pharmacology*
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Rats
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Saimiri
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Sheep
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Emetics
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L-791943
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Phosphodiesterase Inhibitors
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Pyridines
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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Ovalbumin
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4